Pain is a tremendous human health problem accounting for considerable morbidity and even contributing directly to mortality. Clinical pain conditions feature marked gender differences in their frequency and severity. One possible explanation for these differences is that the sexes may be differentially sensitive to pain. Indeed, when differences are found, females - of many species including rodents - appear to be more sensitive to and less tolerant of pain. The greater sensitivity to pain in females is accompanied by reduced sensitivity to analgesic drugs like morphine. Evidence exists suggesting that these quantitative sex differences in pain and analgesic may reflect the activation of qualitatively different pain modulatory systems in each sex. Pharmacological and genetic evidence support the contention that female mice possess a sex-specific, non-opioid analgesic mechanism. The neurochemical identification of this mechanism remains obscure, but a chromosomal region (chromosome 8; greater than 52 cM) has recently been identified that contains a gene which mediates endogenous analgesia in females, but not males. Another sex-specific gene effect, associated with basal sensitivity to acute, thermal nociception and/or opioid analgesia in males but not females, has been localized to chromosome 4 (40-80 cM). Preliminary data suggests that the relevant gene in this region may be Oprdl, which encodes the murine d-opioid receptor. Finally, two inbred mouse strains have been identified that show significant male greater than female (AKR) and female greater than male (CBA) analgesic sensitivity to morphine. The aims of this project are to make forward progress on each of these three sex-specific gene effects: the techniques to be employed are unique to each situation. Quantitative trait locus (QTL) mapping techniques will be applied to morphine analgesia using AKR and CBA strains in a directed attempt to identify female-specific QTLs. Testing of additional genetic populations, including transgenic "knock-out" mice lacking functional expression of the Oprdl gene, will reveal the generalizability of the male-specific chromosome 4 QTL already identified. Finally, initial steps will be taken towards the positional cloning of the female- specific chromosome 8 QTL, in order to characterize the female-specific analgesic mechanism. Clinical applications of this work may include the development of novel and sex-specific analgesic strategies.